Vesicular Monoamine Transporter Type Research Articles

Practical Synthesis of Valbenazine via 1,3‐Dipolar Cycloaddition†

Comprehensive SummaryValbenazine (Ingrezza), a potent and highly selective inhibitor of vesicular monoamine transporter type 2 (VMAT2) through the active metabolite hydrotetrabenazine (HTBZ), has been approved for the treatment of tardive dyskinesia and, very recently, for chorea, which is associated with Huntington's disease. Despite numerous synthetic efforts dedicated to the synthesis of HTBZ, the industrial preparation of valbenazine uses dihydroisoquinoline as a starting material and the chiral resolution of racemic HTBZ derived from ketone reduction. Herein, we present a practical synthesis of HTBZ and valbenazine featuring a highly stereoselective 1,3‐dipolar cycloaddition and enzymatic kinetic resolution. The cascade process includes cycloaddition, N—O bond cleavage, and lactamization, which proved to be operationally simple. The allure of the enzymatic resolution developed in this work offers a rapid access toward affording tetrahydroisoquinoline (THIQ)‐fused piperidine in the production of medically significant compounds, such as yohimbine and reserpine.

GABAA Receptor Benzodiazepine Binding Sites and Motor Impairments in Parkinson's Disease.

Flumazenil is an allosteric modulator of the γ-aminobutyric acid-A receptor (GABAAR) benzodiazepine binding site that could normalize neuronal signaling and improve motor impairments in Parkinson's disease (PD). Little is known about how regional GABAAR availability affects motor symptoms. We investigated the relationship between regional availability of GABAAR benzodiazepine binding sites and motor impairments in PD. Methods: A total of 11 Patients with PD (males; mean age 69.0 ± 4.6 years; Hoehn and Yahr stages 2-3) underwent [11C]flumazenil GABAAR benzodiazepine binding site and [11C]dihydrotetrabenazine vesicular monoamine transporter type-2 (VMAT2) PET imaging and clinical assessment. Stepwise regression analysis was used to predict regional cerebral correlates of the four cardinal UPDRS motor scores using cortical, striatal, thalamic, and cerebellar flumazenil binding estimates. Thalamic GABAAR availability was selectively associated with axial motor scores (R2 = 0.55, F = 11.0, β = -6.4, p = 0.0009). Multi-ligand analysis demonstrated significant axial motor predictor effects by both thalamic GABAAR availability (R2 = 0.47, β = -5.2, F = 7.2, p = 0.028) and striatal VMAT2 binding (R2 = 0.30, β = -3.9, F = 9.1, p = 0.019; total model: R2 = 0.77, F = 11.9, p = 0.0056). Post hoc analysis demonstrated that thalamic [11C]methyl-4-piperidinyl propionate cholinesterase PET and K1 flow delivery findings were not significant confounders. Findings suggest that reduced thalamic GABAAR availability correlates with worsened axial motor impairments in PD, independent of nigrostriatal degeneration. These findings may augur novel non-dopaminergic approaches to treating axial motor impairments in PD.

Using 18F-AV-133 VMAT2 PET Imaging to Monitor Progressive Nigrostriatal Degeneration in Parkinson Disease.

There are limited validated biomarkers in Parkinson disease (PD) which substantially hinders the ability to monitor disease progression and consequently measure the efficacy of disease-modifying treatments. Imaging biomarkers, such as vesicular monoamine transporter type 2 (VMAT2) PET, enable enhanced diagnostic accuracy and detect early neurodegenerative changes associated with prodromal PD. This study sought to assess whether 18F-AV-133 VMAT2 PET is sensitive enough to monitor and quantify disease progression over a 2-year window. 18F-AV-133 PET scans were performed on participants with PD and REM sleep behavior disorder (RBD) and neurologic controls (NC). All participants were scanned twice ∼26 months apart. Regional tracer retention was calculated with a primary visual cortex reference region and expressed as the standard uptake volume ratio. Regions of interest included caudate, anterior, and posterior putamen. At the time of scanning, participants underwent clinical evaluation including UPDRSMOTOR test, Sniffin' Sticks, and Hospital Anxiety and Depression Score. Over the 26-month interval, a significant decline in PET signal was observed in all 3 regions in participants with PD (N = 26) compared with NC (N = 12), consistent with a decrease in VMAT2 level and ongoing neurodegeneration. Imaging trajectory calculations suggest that the neurodegeneration in PD occurs over ∼33 years [CI: 27.2-39.5], with ∼10.5 years [CI: 9.1-11.3] of degeneration in the posterior putamen before it becomes detectable on a VMAT2 PET scan, a further ∼6.5 years [CI: 1.6-12.7] until symptom onset, and a further ∼3 years [CI: 0.3-8.7] until clinical diagnosis. Over a 2-year period, 18F-AV-133 VMAT2 PET was able to detect progression of nigrostriatal degeneration in participants with PD, and it represents a sensitive tool to identify individuals at risk of progression to PD, which are currently lacking using clinical readouts. Trajectory models propose that there is nigrostriatal degeneration occurring for 20 years before clinical diagnosis. These data demonstrate that VMAT2 PET provides a sensitive measure to monitor neurodegenerative progression of PD which has implications for PD diagnostics and subsequently clinical trial patient stratification and monitoring. This study provides Class IV evidence that VMAT2 PET can detect patients with Parkinson disease and quantify progression over a 2-year window.

Valbenazine as treatment for Huntington's disease chorea

Chorea, the prototypical movement disorder in Huntington's disease, is a syndrome characterised by abrupt involuntary movements resulting from a continuous flow of random muscle contractions. 1 Cardoso F Seppi K Mair KJ Wenning GK Poewe W Seminar on choreas. Lancet Neurol. 2006; 5: 589-602 Summary Full Text Full Text PDF PubMed Scopus (220) Google Scholar Symptomatic treatment of chorea in patients with Huntington's disease should be considered when it causes functional disability, discomfort, or social embarrassment. 1 Cardoso F Seppi K Mair KJ Wenning GK Poewe W Seminar on choreas. Lancet Neurol. 2006; 5: 589-602 Summary Full Text Full Text PDF PubMed Scopus (220) Google Scholar One mainstay of pharmacological treatment is to reduce dopaminergic neurotransmission via inhibition of vesicular monoamine transporter type 2 (VMAT2), leading to presynaptic dopamine depletion. 2 Bashir H Jankovic J Treatment options for chorea. Expert Rev Neurother. 2018; 18: 51-63 Crossref PubMed Scopus (31) Google Scholar , 3 Koch J Shi WX Dashtipour K VMAT2 inhibitors for the treatment of hyperkinetic movement disorders. Pharmacol Ther. 2020; 212107580 Crossref Scopus (5) Google Scholar Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trialIn individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea. Full-Text PDF

Cholinergic brain network deficits associated with vestibular sensory conflict deficits in Parkinson's disease: correlation with postural and gait deficits.

To examine regional cerebral vesicular acetylcholine transporter (VAChT) ligand [18F]fluoroethoxybenzovesamicol ([18F]-FEOBV) PET binding in Parkinson' disease (PD) patients with and without vestibular sensory conflict deficits (VSCD). To examine associations between VSCD-associated cholinergic brain deficits and postural instability and gait difficulties (PIGD). PD persons (M70/F22; mean age 67.6 ± 7.4years) completed clinical assessments for imbalance, falls, freezing of gait (FoG), modified Romberg sensory conflict testing, and underwent VAChT PET. Volumes of interest (VOI)-based analyses included detailed thalamic and cerebellar parcellations. VSCD-associated VAChT VOI selection used stepwise logistic regression analysis. Vesicular monoamine transporter type 2 (VMAT2) [11C]dihydrotetrabenazine (DTBZ) PET imaging was available in 54 patients. Analyses of covariance were performed to compare VSCD-associated cholinergic deficits between patients with and without PIGD motor features while accounting for confounders. PET sampling passed acceptance criteria in 73 patients. This data-driven analysis identified cholinergic deficits in five brain VOIs associating with the presence of VSCD: medial geniculate nucleus (MGN) (P < 0.0001), para-hippocampal gyrus (P = 0.0043), inferior nucleus of the pulvinar (P = 0.047), fusiform gyrus (P = 0.035) and the amygdala (P = 0.019). Composite VSCD-associated [18F]FEOBV-binding deficits in these 5 regions were significantly lower in patients with imbalance (-8.3%, F = 6.5, P = 0.015; total model: F = 5.1, P = 0.0008), falls (-6.9%, F = 4.9, P = 0.03; total model F = 4.7, P = 0.0015), and FoG (-14.2%, F = 9.0, P = 0.0043; total model F = 5.8, P = 0.0003), independent of age, duration of disease, gender and nigrostriatal dopaminergic losses. Post hoc analysis using MGN VAChT binding as the single cholinergic VOI demonstrated similar significant associations with imbalance, falls and FoG. VSCD-associated cholinergic network changes localize to distinct structures involved in multi-sensory, in particular vestibular, and multimodal cognitive and motor integration brain regions. Relative clinical effects of VSCD-associated cholinergic network deficits were largest for FoG followed by postural imbalance and falls. The MGN was the most significant region identified.

The selective 5-HT 1A receptor agonist, NLX-112, overcomes tetrabenazine-induced catalepsy and depression-like behavior in the rat.

Tetrabenazine, a preferential inhibitor of the vesicular monoamine transporter type 2, depletes the brain monoamines dopamine, serotonin and norepinephrine. Tetrabenazine and deutetrabenazine (Austedo ®) are used to treat chorea associated with Huntington's disease. However, both compounds are known to aggravate Parkinsonism and depression observed in Huntington's disease patients. NLX-112 (a.k.a. befiradol/F13640) is a highly selective, potent and efficacious serotonin 5-HT 1A agonist. In animal models, it has robust efficacy in combating other iatrogenic motor disorders such as L-DOPA-induced dyskinesia and has marked antidepressant-like activity in rodent tests. In the present study, we investigated, in rats, the efficacy of NLX-112 to counteract tetrabenazine-induced catalepsy (a model of Parkinsonism) and tetrabenazine-induced potentiation of immobility in the forced swim test (FST, a model to detect antidepressant-like activity). The prototypical 5-HT 1A agonist, (±)8-OH-DPAT, and the 5-HT 1A partial agonist/dopamine D2 receptor blocker, buspirone, were used as comparators. Both NLX-112 and (±)8-OH-DPAT (0.16-2.5 mg/kg p.o. or s.c., respectively) abolished catalepsy induced by tetrabenazine (2 mg/kg i.p.). In comparison, buspirone (0.63-5.0 mg/kg p.o.) was ineffective and even tended to potentiate tetrabenazine-induced catalepsy at 0.63 mg/kg. In the FST, NLX-112 and (±)8-OH-DPAT (0.63 mg/kg) strongly reduced immobility when administered alone but also significantly opposed potentiation of immobility induced by tetrabenazine (1.5 mg/kg i.p.). Buspirone (0.63 and 2.5 mg/kg p.o.) had no effect by itself or against tetrabenazine. These results strongly suggest that selective and highly efficacious 5-HT 1A agonists, such as NLX-112, may be useful in combating tetrabenazine-induced Parkinsonism and/or depression in Huntington's disease patients.

No Dopamine Agonist Modulation of Brain [18F]FEOBV Binding in Parkinson's Disease.

The [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) positron emission tomography (PET) ligand targets the vesicular acetylcholine transporter. Recent [18F]FEOBV PET rodent studies suggest that regional brain [18F]FEOBV binding may be modulated by dopamine D2-like receptor agents. We examined associations of regional brain [18F]FEOBV PET binding in Parkinson's disease (PD) subjects without versus with dopamine D2-like receptor agonist drug treatment. PD subjects (n = 108; 84 males, 24 females; mean age 68.0 ± 7.6 [SD] years), mean disease duration of 6.0 ± 4.0 years, and mean Movement Disorder Society-revised Unified PD Rating Scale III 35.5 ± 14.2 completed [18F]FEOBV brain PET imaging. Thirty-eight subjects were taking dopamine D2-like agonists. Vesicular monoamine transporter type 2 [11C]dihydrotetrabenazine (DTBZ) PET was available in a subset of 54 patients. Subjects on dopamine D2-like agonists were younger, had a longer duration of disease, and were taking a higher levodopa equivalent dose (LED) compared to subjects not taking dopamine agonists. A group comparison between subjects with versus without dopamine D2-like agonist use did not yield significant differences in cortical, striatal, thalamic, or cerebellar gray matter [18F]FEOBV binding. Confounder analysis using age, duration of disease, LED, and striatal [11C]DTBZ binding also failed to show significant regional [18F]FEOBV binding differences between these two groups. Chronic D2-like dopamine agonist use in PD subjects is not associated with significant alterations of regional brain [18F]FEOBV binding.

Meta-Analysis: Efficacy and Tolerability of Vesicular Monoamine Transporter Type 2 Inhibitors in the Treatment of Tic Disorders.

Vesicular monoamine transporter type 2 (VMAT2) inhibitors may be an effective therapy for chronic tic disorders (CTD), including Tourette syndrome (TS), but there has not been a meta-analysis compiling available evidence from randomized controlled trials (RCTs). We performed a systematic review and meta-analysis to evaluate the efficacy, acceptability, and tolerability of VMAT2 inhibitors for CTD/TS. PubMed, CENTRAL, and Embase were searched for double-blinded RCTs of VMAT2 inhibitors versus placebo for the treatment of CTD/TS. Change in tic severity measured by the Yale Global Tic Severity Scale (efficacy) and rates of discontinuation attributed to adverse effects (tolerability) or all causes (acceptability) were extracted closest to 12 weeks. Mean difference (MD) and odds ratio (OR) were the effect size indexes for efficacy and acceptability/tolerability, respectively. Data were pooled through random-effects meta-analysis weighted by inverse variance. Five RCTs involving eight comparisons were included. Meta-analysis found a nonsignificant effect on efficacy (k=8; N=583; MD=-0.71; 95% confidence interval [CI], -1.93 to 0.50; P=0.24), and there was certainty that the true effect is nonclinically meaningful (high quality of evidence). Meta-analysis found decreased tolerability (k=7; N=626; OR=2.67; 95% CI, 1.21-5.92; P=0.01) and decreased acceptability (k=8; N=626; OR=1.90; 95% CI, 1.14-3.18; P=0.01), although those comparisons were limited because of the relatively small number of events across trials. Meta-analyses did not support the efficacy of VMAT2 inhibitors in the short-term treatment of tic disorders and suggested no clinically meaningful effect of these agents on tic symptoms. © 2022 International Parkinson and Movement Disorder Society.

PET Imaging of VMAT2 with the Novel Radioligand [18F]FE-DTBZ-d4 in Nonhuman Primates: Comparison with [11C]DTBZ and [18F]FE-DTBZ.

The vesicular monoamine transporter type 2 (VMAT2) is believed to be responsible for the uptake of monoamines into the vesicles of the synaptic terminals. Two VMAT2 radioligands [11C]DTBZ and [18F]FP-DTBZ have been used to assess the degree of nigrostriatal deficit in Parkinson’s disease (PD) using positron emission tomography (PET). [18F]FE-DTBZ-d4, the nondeuterated analogue of [18F]FE-DTBZ showed similar imaging properties with better stability against defluorination. Therefore, [18F]FE-DTBZ-d4 draws attention to be investigated as an imaging marker for VMAT2 in the brain. The aim of this study was to investigate the brain kinetics and quantification of [18F]FE-DTBZ-d4 in nonhuman primates (NHPs), with comparison to [11C]DTBZ and [18F]FE-DTBZ. Radiolabeling was successfully achieved either by one-step 11C-methylation or by a two-step fluorine-18 nucleophilic substitution reaction. The stability and radiochemical yield were analyzed with high-performance liquid chromatography (HPLC). Three female cynomolgus monkeys were included in the study and underwent a total of 12 positron emission tomography (PET) measurements. Each monkey was examined with each tracer. In addition, two pretreatment and one displacement PET measurements with tetrabenazine (2.0 mg/kg) were performed for [18F]FE-DTBZ-d4. All PET measurements were conducted using a high-resolution research tomograph (HRRT) system. Radiometabolites were measured in monkey plasma using gradient radio-HPLC. [18F]FE-DTBZ-d4 (SUV: 4.28 ± 1.01) displayed higher brain uptake compared to both [18F]FE-DTBZ (SUV: 3.43 ± 0.54) and [11C]DTBZ (SUV: 3.06 ± 0.32) and faster washout. Binding potential (BPND) values of [18F]FE-DTBZ-d4 in different brain regions (putamen: 5.5 ± 1.4; caudate: 4.4 ± 1.1; midbrain: 1.4 ± 0.4) were higher than those of [11C]DTBZ and [18F]FE-DTBZ. [18F]FE-DTBZ showed faster radiometabolism in plasma compared to [11C]DTBZ and [18F]FE-DTBZ-d4. [18F]FE-DTBZ-d4 is a suitable radioligand for quantification of VMAT2 in the nonhuman primate brain, with better imaging properties than [11C]DTBZ and [18F]FE-DTBZ. A preliminary comparison suggests that [18F]FE-DTBZ-d4 has increased stability against defluorination compared to the nondeuterated analogue.

Comparisons of vesicular monoamine transporter type 2 signals in Parkinson's disease and parkinsonism secondary to carbon monoxide poisoning

Parkinson’s disease (PD) and carbon monoxide (CO) poisoning demonstrate parkinsonian features related to presynaptic dopaminergic deficits. However, their clinical features and treatment responses are different, indicating other roles of neurotransmitters in symptomatic modulation. In this study, we used 18F-FP-(+)-DTBZ PET to explore vesicular monoamine transporter type 2 (VMAT2) distributions in 31 patients with PD, 39 patients with CO poisoning and parkinsonian features (n = 39), and 24 age-matched controls. In addition to the disease-specific VMAT2 topographies in PD and CO poisoning, we also constructed feature-specific functional networks. The cardinal features included tremor, rigidity, akinesia, and rapid alternating movements (RAM), and the overall motor severity was scored using Unified Parkinson Disease Rating Scale (UPDRS) and modified Hoehn-Yahr (mH-Y) Scale scores. Our results suggested that a reduction in VMAT2 signals in the caudate, amygdala, and hippocampus were more specific to CO poisoning, while low uptake in the putamen and substantia nigra was more specific to PD. UPDRS and mH-Y scores were related to striatum signals in both groups and hippocampus and raphe in the CO poisoning group. With regards to the cardinal features, the putamen was related to akinesia in both groups. The substantia nigra was related to rigidity in PD, and the caudate and nucleus accumbens were related to akinesia, RAM and rigidity in CO poisoning. Our study enhances the current understanding of different patterns of monoaminergic terminal deficits in patients with CO poisoning and PD.

Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia

ABSTRACT Introduction: Tardive dyskinesia (TD) is a hyperkinetic movement disorder that arises as a complication of exposure to dopamine receptor blocking agents. Vesicular monoamine transporter type 2 (VMAT2) inhibitors reduce dyskinesia by decreasing transport of monoamines, including dopamine, into presynaptic vesicles, leaving unpackaged dopamine to be metabolized by monoamine oxidase. Deutetrabenazine was adapted from an earlier VMAT2 inhibitor, tetrabenazine, by substituting three deuterium isotopes in place of three hydrogen isotopes at the site of metabolic degradation to improve upon the pharmacokinetics of the parent compound. Areas covered: The authors reviewed the pivotal trials examining the safety and efficacy of deutetrabenazine, as well as long-term data from an open-label extension. Also reviewed were posters and oral presentations, as well as information from the product label and the United States Food and Drug Administration. Expert opinion: Deutetrabenazine is effective at decreasing dyskinesia in TD, but drug selection and cost-effectiveness between existing VMAT2 inhibitors are evolving areas of study. Other areas of investigation include novel anti-dyskinetic agents and use of deep brain stimulation.

The Gene Polymorphism of VMAT2 Is Associated with Risk of Schizophrenia in Male Han Chinese.

ObjectiveTo investigate the association between gene polymorphism of vesicular monoamine transporter type 2(VMAT2) and schizophrenia in Han Chinese population. Methods430 patients with schizophrenia and 470 age-sex matched controls were recruited from four mental health centers. All patients were diagnosed by two psychiatrists based on the Structured Clinical Interview for DSM Disorders (SCID). The ligase detection reactions (LDR) method was used to assess the polymorphism of the two SNPs (rs363371 and rs363324) of VMAT2. ResultsNo associations of two SNPs with schizophrenia was found. When we stratified males and females for the analysis, we found that that in the recessive model of rs363371, there was an obvious significant association between rs363371 and schizophrenia in males (OR=0.564, 95% CI=0.357–0.892, p=0.014) but not females. For the association between rs363324 and schizophrenia, no association was found in either males or females. No association was found when stratifying early-onset schizophrenia and late-onset schizophrenia. ConclusionOur findings indicate that both rs363371 and rs363324 were not associated with schizophrenia, while it seemed that the AA genotype of rs363371 plays a protective effect in male Chinese in developing schizophrenia.

Reduced striatal vesicular monoamine transporter 2 in REM sleep behavior disorder: imaging prodromal parkinsonism

Motor deficits in parkinsonism are caused by degeneration of dopaminergic nigral neurons. The success of disease-modifying therapies relies on early detection of the underlying pathological process, leading to early interventions in the disease phenotype. Healthy (n = 16), REM sleep behavior disorder (RBD) (n = 14), dementia with Lewy bodies (n = 10), and Parkinson’s disease (PD) (n = 20) participants underwent 18F-AV133 vesicular monoamine transporter type-2 (VMAT2) PET to determine the integrity of the nigrostriatal pathway. Clinical, neurophysiological and neuropsychological testing was conducted to assess parkinsonian symptoms. There was reduced VMAT2 levels in RBD participants in the caudate and putamen, indicating nigrostriatal degeneration. RBD patients also presented with hyposmia and anxiety, non-motor symptoms associated with parkinsonism. 18F-AV133 VMAT2 PET allows identification of underlying nigrostriatal degeneration in RBD patients. These findings align with observations of concurrent non-motor symptoms in PD and RBD participants of the Parkinson’s Progression Markers Initiative. Together, these findings suggest that RBD subjects have prodromal parkinsonism supporting the concept of conducting neuroprotective therapeutic trials in RBD-enriched cohorts. Ongoing longitudinal follow-up of these subjects will allow us to determine the time-window of clinical progression.

PND2 A Meta-Analysis of Efficacy and Safety of Vesicular Monoamine Transporter Type 2 Inhibitors for Treatment of Huntington Chorea

PND2 A Meta-Analysis of Efficacy and Safety of Vesicular Monoamine Transporter Type 2 Inhibitors for Treatment of Huntington Chorea

PET imaging with [18F]FP-(+)-DTBZ in 6-OHDA-induced partial and full unilaterally-lesioned model rats of Parkinson's disease and the correlations to the biological data

ObjectiveThe deficit of dopaminergic neurons in the nigrostriatal pathway is one of the pathological features of Parkinson's disease (PD). The decline of vesicular monoamine transporter type 2 (VMAT2) has been verified to relate with the severity of PD. The purpose of this study was to evaluate the ability of [18F]fluoropropyl-(+)-dihydrotetrabenazine ([18F]FP-(+)-DTBZ) to detect dopaminergic neuron dysfunction in a standard rat model of PD using PET imaging. Specifically, two different doses of 6-hydroxydopamine (6-OHDA) were injected unilaterally into the medial forebrain bundle (MFB) to create the models with two different severities. MethodsMale Sprague-Dawley rats were intracranially injected with 8 μg 6-OHDA (partial lesion group), 16 μg 6-OHDA (full lesion group) and vehicle (sham group) into MFB, respectively. Thirty minutes static [18F]FP-(+)-DTBZ microPET scanning was performed to determine the dopaminergic neuron integrity on the 28th day post-injection and the behavioral tests were carried out in the next two days. Then, the rats were decapitated, and the brains were collected for biogenic amines content analysis or dissected for autoradiography and immunohistochemical (IHC) staining. The correlations of PET results to the behavioral, biological, histological, autoradiography results were analyzed, respectively. ResultsThe standardized uptake value ratio (ST to CB) of [18F]FP-(+)-DTBZ in the ipsilateral striata decreased significantly in partial lesion group and full lesion group. Compared with the sham group, the ratio of the standardized uptake value in ipsilateral striatum to that in contralateral striatum decreased by 57.09 ± 2.30% (full lesion group) and 25.31 ± 5.70% (partial lesion group), respectively. The dopaminergic neuronal dysfunction was corroborated by in vitro autoradiography, IHC, and quantitative analysis of DA as well as its metabolites concentration tests. The motor function impairments of 6-OHDA-treated animals were manifested by a series of behavioral tests. The results of microPET imaging were linearly correlated with behavioral, biological, histological, and autoradiography results, respectively. ConclusionOur data suggest that [18F]FP-(+)-DTBZ may be useful for detecting different degrees of dopaminergic neuronal lesions by PET imaging in PD models induced by 6-OHDA.

Management of Tardive Syndrome: Medications and Surgical Treatments.

Tardive syndrome (TS) is an iatrogenic, often persistent movement disorder caused by drugs that block dopamine receptors. It has a broad phenotype including movement (orobuccolingual stereotypy, dystonia, tics, and others) and nonmotor features (akathisia and pain). TS has garnered increased attention of late because of the Food and Drug Administration approval of the first therapeutic agents developed specifically for this purpose. This paper will begin with a discussion on pathogenesis, clinical features, and epidemiology. However, the main focus will be treatment options currently available for TS including a suggested algorithm based on current evidence. Recently, there have been significant advances in TS therapy, particularly with the development of 2 new vesicular monoamine transporter type 2 inhibitors for TS and with new data on the efficacy of deep brain stimulation. The discussion will start with switching antipsychotics and the use of clozapine monotherapy which, despite the lack of higher-level evidence, should be considered for the treatment of psychosis and TS. Anti-dyskinetic drugs are separated into 3 tiers: 1) vesicular monoamine transporter type 2 inhibitors, which have level A evidence, are approved for use in TS and are recommended first-choice agents; 2) drugs with lower level of evidence for efficacy including clonazepam, Ginkgo biloba, and amantadine; and 3) drugs that have the potential to be beneficial, but currently have insufficient evidence including levetiracetam, piracetam, vitamin B6, melatonin, baclofen, propranolol, zolpidem, and zonisamide. Finally, the roles of botulinum toxin and surgical therapy will be examined. Current therapies, though improved, are symptomatic. Next steps should focus on the prevention and reversal of the pathogenic process.

A Focused Update on Tardive Dyskinesia.

Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication following chronic exposure to centrally acting dopamine receptor antagonists, mainly of the class of antipsychotics drugs. New generations of antipsychotic drugs reduced its mean prevalence to 20%, but it continues to mar the drug experience and social integration in a significant fraction of patients. The underlying molecular cascade remains elusive, explaining in part why TD management is so often difficult. Protocol variations between experimental laboratories and inter-species differences in the biological response to antipsychotic drugs have added layers of complexity. The traditional dopamine D2 receptor supersensitivity hypothesis was revisited in an experimental nonhuman primate model. Findings in the striatum revealed a strong upregulation of D3, not D2, receptors specific to dyskinetic animals, and indirect evidence suggestive of a link between overactivation of glycogen synthase kinase-3β signaling and TD. New effective vesicular monoamine transporter type 2 inhibitors alleviating TD have been approved in the USA. They were integrated to an emerging stepwise treatment algorithm for troublesome TD, which also includes consideration for changes in the current antipsychotic drug regimen and recognition of potentially aggravating factors such as anticholinergic co-medications. These advances may benefit TD.

Chronic Neuroleptic-Induced Parkinsonism Examined With Positron Emission Tomography.

Neuroleptic drug-induced parkinsonism (NIP) is a leading cause of parkinsonism, particularly in aging. Based on abnormal dopamine transporter scan results, individuals displaying chronic NIP are often diagnosed with Lewy-body Parkinson's disease (PD), but this assumption needs further substantiation. To quantitate the profile of striatal dopaminergic nerve terminal density in NIP relative to PD. We used the positron emission tomography ligand [11 C](+)-dihydrotetrabenazine targeting vesicular monoamine transporter type 2 (VMAT2) binding sites and collected various clinical parameters (motor ratings, olfaction, polysomnography to document rapid eye movement sleep muscle activity, quantitative sensory testing for pain thresholds) possibly predicting binding results in patients older than age 50 living with schizophrenia spectrum disorders under long-term stable antipsychotic drug treatment, with (N = 11) or without (N = 11) chart documention of chronic NIP, and compared them to healthy volunteers (N = 11) and others medicated for PD (N = 12). Striatal VMAT2 binding was dichotomous in the NIP group between those with spared (N = 5) or low (N = 6) PD-like values. Striatal binding reduction in the low VMAT2-NIP group was asymmetric without the gradient of maximal involvement in the posterior putamen typical of PD. Anosmia was the only nonmotor parameter measured matching the abnormal striatal VMAT2 binding status. These preliminary observations suggest that striatal VMAT2 binding is abnormal in a fraction of chronic NIP cases and differs in spatial distribution from PD. The possibility of a drug-induced axonopathy and resultant synaptopathy, as well as the evolution of the binding deficit, warrant further longitudinal studies in a large cohort. © 2020 International Parkinson and Movement Disorder Society.

152 Development of Deutetrabenazine as a Potential New Non-Antipsychotic Treatment for Tourette Syndrome in Children and Adolescents

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by the hyperkinetic movements of motor and phonic tics manifested in young age. Currently approved treatments in the United States are antipsychotics: haloperidol, pimozide, and aripiprazole, which are associated with serious side effects, including tardive dyskinesia (TD). Deutetrabenazine, a vesicular monoamine transporter type 2 (VMAT2) inhibitor, was approved in 2017 by the US FDA for the treatment of chorea associated with Huntington's disease and TD. Three ongoing studies (Alternatives for Reducing Tics in TS [ARTISTS]) are evaluating the efficacy, safety, and tolerability of deutetrabenazine in reducing tics in TS in children and adolescents (age 6-16 years). ARTISTS 1, a phase 2/3, response-driven, dose-titration, placebo-controlled study, randomizes patients (N=116) 1:1 to deutetrabenazine or placebo for 12 weeks. ARTISTS 2, a phase 3, fixed-dose study, randomizes patients (N=150) 1:1:1 to deutetrabenazine high or low dose, or placebo for 8 weeks. The primary efficacy outcome in these pivotal studies is change from baseline to end of treatment in the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). Additional efficacy endpoints and safety/tolerability are also evaluated. ARTISTS is a 56-week, open-label, single-arm, long-term safety/tolerability study in patients who have successfully completed either ARTISTS 1 or ARTISTS 2. Not available yet. TS can have potentially long-term life impact, and there remains unmet medical need for effective and well-tolerated treatments. Three ARTISTS studies will evaluate the efficacy, safety, and tolerability of deutetrabenazine in patients with tics in TS. The studies are sponsored by Teva Pharmaceuticals and operationalized by Teva's development partner, Nuvelution TS Pharma INC.

Synthesis of Tetrabenazine and Its Derivatives, Pursuing Efficiency and Selectivity.

Tetrabenazine is a US Food and Drug Administration (FDA)-approved drug that exhibits a dopamine depleting effect and is used for the treatment of chorea in Huntington’s disease. Mechanistically, tetrabenazine binds and inhibits vesicular monoamine transporter type 2, which is responsible for importing neurotransmitters from the cytosol to the vesicles in neuronal cells. This transportation contributes to the release of neurotransmitters inside the cell to the synaptic cleft, resulting in dopaminergic signal transmission. The highly potent inhibitory activity of tetrabenazine has led to its advanced applications and in-depth investigation of prodrug design and metabolite drug discovery. In addition, the synthesis of enantiomerically pure tetrabenazine has been pursued. After a series of research studies, tetrabenazine derivatives such as valbenazine and deutetrabenazine have been approved by the US FDA. In addition, radioisotopically labeled tetrabenazine permits the early diagnosis of Parkinson’s disease, which is difficult to treat during the later stages of this disease. These applications were made possible by the synthetic efforts aimed toward the efficient and asymmetric synthesis of tetrabenazine. In this review, various syntheses of tetrabenazine and its derivatives have been summarized.